Gut relief revisited: plecanatide in chronic idiopathic constipation and irritable bowel syndrome with constipation — a systematic review and meta-analysis with GRADE assessment

Abstract

Background

Chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C) are prevalent gastrointestinal disorders with limited effective treatment options. CIC affects approximately 14% of the population worldwide, particularly women, and is marked by difficult defecation, while IBS-C also includes abdominal pain as a core of symptom. Plecanatide, a guanylate cyclase-C (GC-C) agonist approved in 2017, has shown promise in improving stool consistency and symptoms; however, its optimal therapeutic dose remains unclear.

Methods

A comprehensive literature search was conducted through (PubMed, Cochrane CENTRAL, Scopus, Web of Science, and Embase) for randomized controlled trials comparing plecanatide with placebo until August 2025. Primary outcomes included changes in complete spontaneous bowel movements (CSBMs), spontaneous bowel movements (SBMs), and stool consistency.

Results

Plecanatide significantly increased the changes in complete spontaneous bowel movements (CSBMs) across all reported doses with mean differences (MDs) of (0.75, 0.92, 0.80, and 1.00, (P < 0.00001), with the greatest improvement observed at the 9 mg dose. Moreover, spontaneous bowel movements (SBMs) improved significantly at 1, 3, and 6 mg, with (MDs: 0.97, 1.50, and 1.58, (P < 0.00001). Stool consistency and reduction in abdominal pain and bloating were observed particularly at 3–6 mg. Furthermore, plecanatide demonstrated consistent efficacy across all doses, with both 1 mg and 9 mg showing significantly greater improvements in CSBMs and SBMs compared to the 0.3 mg dose. Diarrhea was the most frequent adverse event and the primary reason for treatment discontinuation, while other safety outcomes were not significantly affected.

Conclusion

Plecanatide is generally well-tolerated in the treatment of CIC and IBS-C, with the 3 mg dose, offering the best balance between efficacy and safety. This meta-analysis supports its use as a viable treatment option, though diarrhea remains a dose-related concern.

Trial registration

This systematic review and meta-analysis was registered prospectively with PROSPERO (Registration number: CRD420251066097, Date of registration: 2025-6-10).

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12876-026-05112-w.

Introduction

Functional gastrointestinal disorders (FGIDs), recently redefined as disorders of gut–brain interaction, are chronic conditions characterized by persistent gastrointestinal symptoms (GIS) without identifiable structural or significant biochemical abnormalities [1, 2]. Among the most prevalent FGIDs are irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC), both of which contribute substantially to global gastrointestinal morbidity and healthcare burden. Although these conditions share overlapping etiological mechanisms, important clinical differences exist [3, 4]. IBS-C is defined by recurrent abdominal pain associated with altered bowel habits, with constipation as the predominant symptom, whereas CIC is characterized by infrequent or difficult defecation in the absence of significant abdominal pain or organic pathology [1, 5]. Despite being historically classified as distinct disorders, diagnostic overlap between IBS-C and CIC is common and may contribute to misclassification in clinical practice [1, 5] According to the Rome IV criteria, CIC affects approximately 14% of the global population and is more prevalent among females and older adults, particularly those over 50 years of age [2, 5, 6]. In contrast, IBS-C has a lower estimated prevalence of 4–10% but similarly shows a higher incidence in females, especially in individuals with prior gastrointestinal infections or psychological stress [4, 7]. Constipation symptoms are also reported in up to 30% of patients with inflammatory bowel disease (IBD), particularly during remission, often related to medication use, dietary factors, or motility disturbances [8]. The pathogenesis of IBS-C and CIC is multifactorial and involves visceral hypersensitivity, alterations in intestinal motility, gut microbiota dysbiosis, mucosal immune activation, and disturbances in the gut–brain axis [2, 4]. CIC is additionally associated with delayed colonic transit, pelvic floor dysfunction, and lifestyle factors such as low dietary fiber intake and physical inactivity [5, 6]. These conditions significantly impair health-related quality of life (HRQoL), with impacts comparable to chronic inflammatory diseases such as Crohn’s disease (CD) [3], and are associated with considerable healthcare costs, with IBS-C expenditures in the United States estimated to exceed $11,000 per patient annually [9]. Management of IBS-C and CIC typically begins with lifestyle modifications, including increased dietary fiber intake, adequate hydration, and regular physical activity, although these strategies often provide limited relief [5, 10]. Pharmacologic treatments include bulk-forming agents, osmotic and stimulant laxatives, secretagogues such as linaclotide and lubiprostone, and serotonergic agents including prucalopride [11, 12]. Non-pharmacologic options such as biofeedback therapy may benefit patients with defecatory disorders, while probiotics remain under investigation with limited strain-specific evidence [13].

Plecanatide is a synthetic 16–amino acid peptide structurally similar to uroguanylin (UG), an endogenous activator of guanylate cyclase-C (GC-C) receptors [14]. By activating GC-C receptors on intestinal epithelial cells, plecanatide increases intracellular cyclic guanosine monophosphate (cGMP), stimulating chloride and bicarbonate secretion through cystic fibrosis transmembrane conductance regulator (CFTR) channels. This mechanism enhances intestinal fluid secretion, softens stool, and accelerates intestinal transit while exhibiting minimal systemic absorption [15, 16]. Approved by the U.S. Food and Drug Administration (FDA) in 2017 for CIC and later for IBS-C, plecanatide has demonstrated significant improvements in stool frequency, stool consistency, and overall symptom severity in randomized controlled trials [15–17]. Emerging evidence also suggests that GC-C signaling may support mucosal integrity and modulate inflammation, indicating potential relevance in patients with IBS experiencing constipation.

symptoms [15, 18]. Therefore, this systematic review and meta-analysis aim to comprehensively evaluate the efficacy and safety of plecanatide in adults with IBS-C and CIC based on evidence from randomized controlled trials.

Methods

Search strategy

All steps of this comprehensive analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Cochrane Handbook for Systematic Reviews of Interventions [19]. This study was prospectively registered in PROSPERO under the registration number CRD420251066097. We retrieved data from PubMed, Cochrane CENTRAL, Scopus, Web of Science, and Embase, with the search conducted until August 2025.

We applied a comprehensive search strategy using the following terms: Plecanatide OR “Trulance OR SP-304” AND “Irritable Bowel Syndromes” OR IBS OR IBS-C OR “Irritable bowel syndrome” OR “Constipation” OR “Irritable colon” OR “Colitis” OR “Colitides” OR “Mucous colitis” OR “Idiopathic constipation” OR “Chronic constipation” OR “Dyschezia.” [See supplemental index, S1]. In addition, a manual search of the reference lists of relevant articles was performed to identify any additional eligible studies.

Eligibility criteria

Inclusion and exclusion criteria of included studies

Our systematic review included randomized controlled trials involving adult patients (≥ 18 years) diagnosed with chronic idiopathic constipation (CIC) or other forms of chronic constipation (CC), as defined by the Rome II, III, or IV criteria. Studies enrolling patients with chronic constipation (CC) or irritable bowel syndrome with constipation (IBS-C) were eligible. Given the shared mechanism of action and approved therapeutic use of plecanatide in both disorders. To avoid confounding the efficacy estimates, we performed prespecified subgroup analyses by population (CIC vs. IBS-C), while safety outcomes were synthesized across all eligible trials.

Studies were required to report at least one efficacy or safety outcome of interest. Trials involving pediatric populations, non-randomized study designs, animal studies, reviews, editorials, conference abstracts without sufficient data, and studies lacking relevant outcome measures were excluded.

Inclusion of multiple doses

Eligible studies evaluated plecanatide, a guanylate cyclase-C (GC-C) agonist, at doses of 0.3, 1, 3, 6, or 9 mg/day versus placebo. All investigated doses were included to characterize the dose–response relationship for both efficacy and safety and to capture the complete body of randomized evidence. As several trials were designed as dose-ranging studies conducted before the approval of the 3 mg/day regimen, excluding non-approved doses would have omitted relevant randomized data and potentially biased the pooled estimates, and precluded a comprehensive evaluation of efficacy and safety across the therapeutic dose range.

The primary outcomes

(I) the change in Complete Spontaneous Bowel Movements (CSBMs) and Spontaneous Bowel Movements (SBMs) per week and global sustained response, (II) symptom improvement, including straining score, weekly change in stool consistency measured by the Bristol Stool Form Scale (BSFS).

The secondary outcomes

(I) overall response in CSBMs and SBMs following 24 h. (II) change in abdominal pain and bloating, (III) constipation severity and quality of life measurement (PAC-QOL, IBS-QOL), including : patient satisfaction and discontinuation scores. Additionally, we addressed safety-related outcomes, including (I) treatment-emergent adverse events (TEATs), (II) total patients who reported at least ≤ 1 TEATs, (III) incidence of diarrhea, (IV) other adverse events (AEs) such as headache and nasopharyngitis, (V) serious or severe related events (VI) patients- treatment withdrawal.

We also excluded (I) literature, (II) non-relevant original studies, including secondary research, (III) irrelevant data and observational studies, (IV) studies with different interventions, (V) non-randomized (VI) animal studies, and (VII) editorials and non-English studies.

Studies selection

The study selection process was conducted independently by the study authors. During the first stage, two reviewers independently screened the titles and abstracts of the retrieved records to determine their eligibility according to the predefined inclusion criteria. Studies were categorized as eligible, unclear, or excluded. Screening was performed using EndNote (version 21) and Rayyan software [20]. In the second stage, the full texts of the potentially eligible studies were independently reviewed by two authors to determine final inclusion. Any discrepancies between reviewers resolved by a third reviewer. No restrictions were placed on the publication date, and studies published until August 2025 were included. Duplicates were removed using EndNote software, and the study selection process was documented in Microsoft Excel.

Data extraction

Data from the eligible studies were independently and blindly extracted by two reviewers using a standardized Google Excel sheet. Cross-verification was performed, and discrepancies were resolved through discussions. The standardized Google sheet captured information across four key domains, including the following previously mentioned data: changes in the frequency of CSBMs and SBMs per week, global sustained response, overall response in CSBMs and SBMs after 24 h, strain score, changes in BSFS per week, and changes in abdominal pain and bloating. Data on related adverse events, including diarrhea and patient withdrawals, were also collected. The standardized extraction sheet was organized into three main domains.

• (I)Characteristics of the included studies, including sample size, trial number, patient characteristics, plecanatide dose, follow-up duration, and outcome assessment for each study.
• (II)baseline characteristics of the included patients, including age, sex, BMI, and baseline parameters such as CSBMs, SBMs, straining score, BSFS, abdominal pain, and bloating.
• (III)Third domain was based on the clinical and safety outcomes that were predefined clearly in the inclusion criteria.
• (IV)An additional domain was included for studies that reported multiple plecanatide doses. In these cases, data were extracted separately for each dose group, and the results were stratified by dose to examine potential dose-response effects.

Risk of Bias (ROB)

Three blinded investigators independently assessed the quality of the included studies using the Cochrane Collaboration’s Risk of Bias tool (version 2) [21]. This tool evaluates the overall quality of studies across five key domains: the randomization process, bias due to deviations from the intended interventions, bias related to missing outcome data, bias due to improper measurement of outcomes, and bias due to selective reporting of results. Investigators classified the risk of bias for each domain as ‘Low risk,’ ‘Some concerns,’ or ‘High risk.’ Studies were considered to have a low risk of bias if all domains were rated as low risk, whereas studies with some concerns or high risk were flagged if any of the domains were rated as high risk. Any disagreements between the investigators were resolved by a third reviewer. The summary.

and graph of the ROB assessment were generated using Review Manager Software (RevMan, version 5.4 for Windows) [22].

Data analysis

We performed the statistical analyses using Review Manager (RevMan, version 5.4 for Windows) [22]. Continuous outcomes were analyzed using mean differences (MD), while dichotomous outcomes were assessed using risk ratios (RR) with 95% confidence intervals (CI). A random-effects model (DerSimonian–Laird) was applied for all analyses to account for potential heterogeneity among studies. Statistical heterogeneity was assessed using visual inspection of forest plots, the Cochrane Q (chi-square) test, and Higgins and Thompson’s I² statistic. Heterogeneity was considered low, moderate, or high when I² values were < 25%, 25–75%, or > 75%, respectively [23]. Sensitivity analyses were conducted by excluding one study at a time or performing subgroup analyses when appropriate. For studies evaluating multiple plecanatide doses, each dose arm was analyzed separately using pairwise comparisons with a common comparator (placebo).

To explore potential sources of clinical heterogeneity, subgroup analyses were performed according to patient population (CIC versus IBS-C). Additional subgroup analyses were conducted according to plecanatide dose where sufficient data were available. Publication bias was assessed selectively for outcomes with a sufficient number of included studies (≥ 10), in accordance with the PRISMA guidelines.

Extended data, and all figures labeled with an “S” (e.g., Fig. S2 to S43) are available in the Supplemental Index file.

Certainty of evidence

The certainty of evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. The GRADE evaluation, conducted by [Menna M. Aboelkhier], considered multiple domains, including risk of bias, inconsistency, and publication bias, and classified the certainty of evidence as high, moderate, low, or very low. All assessments were independently cross-checked by a second author to ensure accuracy and consistency. The results are summarized in [Supplemental Tables], reporting the certainty of evidence for plecanatide compared with placebo and across different dose regimens.

Results

Literature search

This comprehensive review evaluates the efficacy and safety of the GC-C agonist plecanatide in alleviating abdominal discomfort associated with CIC in patients both with and without coexisting irritable bowel syndrome (IBS). Our search retrieved 991 records, of which 611 remained after removing duplicates. Screening titles and abstracts led to 55 full-text articles assessed for eligibility, with 15 trials included in the systematic review and 13 in the meta-analysis. No additional studies were identified through manual reference review. The PRISMA flow diagram is shown in (Figure 1).

Fig. 1.

PRISMA flow diagram illustrating the study selection process for the systematic review and meta-analysis. The diagram shows the number of records identified, screened, excluded, and included at each stage, along with reasons for exclusion

Characteristics of included studies

Fifteen randomized controlled trials [24–35], including NCT01053962, involved 15,442 adults with CIC, with or without IBS. See Table [1] Most participants were female (63.1%) and aged 18–50 years. Baseline mean abdominal pain scores were 4.13 (± 1.29) for the treatment group and 4.20 (± 1.27) for controls; straining scores were 4.10 and 4.12, and CSBMs were 1.97 (1.44) and 1.93 (1.36) respectively. Key characteristics are summarized .See Table [2].

Table 1.

Summary of the studies included in the meta-analysis

Study ID	Setting	Study Design	Target Population	Intervention & Dose (mg/d)	Comparator	Follow- up Duration	Assessment Outcomes	Main Findings	Sample Size
									Plecanatide	Placebo	Total
Miner 2013 [27]	USA2013	Multi-center [1] RCT	Patients with Chronic Idiopathic Constipation (CIC)	Plecanatide0.3/1/3 mg	Placebo	12 weeks	Overall study responders	Plecanatide in a dose of 3 mg is safe, well tolerated and effective in the treatment of [2].	-	-	946
Miner 2014 [28]	USA2014	Multi-center double RCT NCT01722318	Patients with IBS-C	Plecanatide0.3/ 1.0/ 3.0/ 9.0 mg	Placebo	12 weeks	Overall responder endpoint for [3] IBS-C / change in CSMB, abdominal pain, and stool consistency from baseline	Plecanatide was safe, well-tolerated and rapidly improved bowel habits and abdominal pain in patients with IBS-C.	268	68	336
Rao 2016 [29]	USA2016	double-blind, placebo-controlled trials.	Patients with Chronic Idiopathic Constipation (CIC)	Plecanatide3/6 mg	Placebo	12 weeks	The proportion of durable overall CSBM responders.	Plecanatide significantly improved primary and secondary end points with low incidence of adverse events which makes Plecanatide a promising new treatment for CIC.	1786	897	2683
Miner 2017 [24]	USA & Canada 2013-2015	multicenter, double-blind, placebo-controlledNCT01982240	Male and female (not pregnant or lactating) patients with CIC aged 18-80 years who had body mass index of 18-40 kg/m2	Plecanatide3/6 mg	Placebo	12 weeks	Percentage of patients who were durable overall CSBM responders during the 12-week treatment period. A CSBM weekly responder was defined as a patient who had ≥3 CSBMs for a given week and an increase from baseline of ≥1 CSBM for that same week.	With a minimal incidence of side effects, Plecanatide significantly reduced constipation and its associated symptoms. According to these findings, Plecanatide may prove to be a beneficial therapeutic alternative for the treatment of CIC.	894	452	1346
DeMicco 2017 [25]	USA 2014-2015	randomized, double-blind, placebo-controlled, parallel-studyNCT02122471	Male and female patients aged 18-80 years with CIC(inclusive) and with a body mass index of 18–40 kg/m2	Plecanatide3/6 mg	Placebo	12 weeks	Changes from baseline in mean weekly CSBMs, SBMs, straining scores, and stool consistency.	Plecanatide significantly improved the percentage of durable overall CSBM responders, stool frequency and secondary endpoints. Plecanatide waswell tolerated with low rate of diarrhea, being the most common adverse event.	892	455	1347
Fogel 2018 (a) [30]	USA 2018	Multi-center double RCT	IBS-C patients with history of constipation and abdominal pain for 6 months, including hard/lumpy stools for 25% of defecations, loose/watery stoolsfor 25% of defecations, and abdominal pain/discomfort for 3 days/month in the last 3 months.	Plecanatide3/6 mg	Placebo	12 weeks	Percentage of overall responders during the 12-week treatment.	These clinical studies indicate Plecanatide may offer a promising new treatment for patients with IBS-C.	701	354	1055
Fogel 2018 (b) [32]	USA 2019	Multi-center double RCT	IBS-C patients with history of constipation and abdominal pain for 6 months, including hard/lumpy stools for 25% of defecations, loose/watery stoolsfor 25% of defecations, and abdominal pain/discomfort for 3 days/month in the last 3 months.	Plecanatide3/6 mg	Placebo	12 weeks	Percentage of overall responders during the 12-week treatment.	These clinical studies indicate Plecanatide may offer a promising new treatment for patients with IBS-C.	756	379	1135
Brenner 2018 (a) [31]	USA 2016	double-blind, placebocontrolled trialsNCT02387359	Males and females aged 18-85 years with a body mass index of 18-40 kg/m2 and who met Rome III criteria for IBS-C	Plecanatide3/6 mg	Placebo	12 weeks	Percentage of overallresponders, as based on the FDA guidance of 2012 change frombaseline in stool consistency, and mean change from baselinein straining severity. Additional secondary end points included:percentage of abdominal pain responders.	With few related adverse effects and excellent tolerance, Plecanatide markedly reduced the symptoms of IBS-C's constipation and stomach pain.	698	354	1052
Brenner     2018 (b) [31]	USA 2016	double-blind, placebocontrolled trialsNCT02493452	Males and females aged 18-85 years with a body mass index of 18-40 kg/m2 and who met Rome III criteria for IBS-C	Plecanatide3/6 mg	Placebo	12 weeks	Percentage of overallresponders, as based on the FDA guidance of 2012 change frombaseline in stool consistency, and mean change from baselinein straining severity. Additional secondary end points included:percentage of abdominal pain responders.	With few related adverse effects and excellent tolerance, Plecanatide markedly reduced the symptoms of IBS-C's constipation and stomach pain.	754	376	1130
Brenner 2019 [32]	USA2019	Multi-center double RCT	Patients with Chronic Idiopathic Constipation (CIC)	Plecanatide3/6 mg	Placebo	12 weeks	Patient Assessment of Constipation–Quality of Life (PAC-QOL [4]) scales, respectively. The PAC-SYM measured patients’ constipation symptom experience and severity over time, including abdominal, rectal, and stool symptoms of constipation.	Plecanatide in both doses of 3mg and 6mg significantly improved global constipation symptoms and HRQOL [5]. Plecanatide was well tolerated with a low incidence of adverse events.	1786	897	683
Bareish 2020 [26]	USA 2020	randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study NCT01429987	Patients aged 18-75 years and diagnosed with CIC based on modified Rome III criteria (< 3 complete spontaneous bowel movements [CSBMs] per week and infrequent loose stools without the use of laxatives)	Plecanatide 0.3/1/3 mg	Placebo	12 weeks	Proportion of overall [6] CSBM responders.change in CSBM and spontaneous bowel movement ([7] SBM) frequency rates, patient-reported outcomes, safety, and tolerability.	Plecanatide is a well-tolerated medication that reduced CIC symptoms with a comparatively low incidence of diarrhea	567	171	738
Cash 2021(a) [33]	USA2021	Multi-center double RCT	Patients with Chronic Idiopathic Constipation (CIC)	Plecanatide 3mg	Placebo	12 weeks	CSBMs/week, spontaneous bowel movements (SBMs)/week, stool consistency (BristolStool Form Scale), straining, abdominal pain, and bloating.	Plecanatide significantly improved both abdominal and bowel symptoms in comparison to placebo in severely constipated CIC / IBS-C patients who constituted 25% of patients enrolled in the trials.	220	213	433
Cash 2021 (b) [33]	USA2022	Multi-center double RCT	Patients with Chronic Idiopathic Constipation (CIC) and IBS-C	Plecanatide 3mg	Placebo	12 weeks	CSBMs/week, spontaneous bowel movements (SBMs)/week, stool consistency (BristolStool Form Scale), straining, abdominal pain, and bloating.	Plecanatide significantly improved both abdominal and bowel symptoms in comparison to placebo in severely constipated CIC / IBS-C patients who constituted 25% of patients enrolled in the trials.	188	168	356
NCT01053962 2010 [34]	USA 2010	Multi-center double RCT NCT01053962	Patients with Chronic Idiopathic Constipation (CIC)	Plecanatide 0.3/1/3/ 9 mg	Placebo	3 weeks	Changes from baseline in mean weekly CSBMs, SBMs, straining scores, and stool consistency	With few related adverse effects and excellent tolerance, Plecanatide markedly reduced the symptoms of IBS-C's constipation and stomach pain.	58	20	78
NCT03120520 2019 [35]	USA 2019	Multi-center double RCT NCT03120520	Adolescents 12 to <18 Years of Age with Chronic Idiopathic Constipation	Plecanatide 0.5/1/1.5 mg	Placebo	8 weeks	Changes from baseline in mean weekly CSBMs, SBMs, straining scores, and stool consistency	Plecanatide was well tolerated with minimal incidence of adverse events and discontinuation.	93	31	124

^aRCT randomized controlled trial

^bCIC chronic idiopathic constipation

^cIBS-C irritable bowel syndrome with constipation

^dPAC-QOL Patient Assessment of Constipation

^eQuality of Life, HRQOL health-related quality of life.

^fCSBM complete spontaneous bowel movement

^gSBM spontaneous bowel movement

^hSD standard deviation

ⁱBMI body mass index

^jPLE Plecanatide, PCB Placebo

Table 2.

Baseline patient characteristics of the studies included in the meta-analysis

Study ID	Study Groups	Age (Years)		Gender (Female n%)		BMI[2] (Kg/m2)		CSBMs/week
		(Mean/SD[1])				(Mean/SD)		(Mean/SD)
		Plecanatide	Control	Plecanatide	Control	Plecanatide	Control	Plecanatide	Control
Miner 2013 [27]	-	-	-	-	-	-	-	-	-
Miner 2014 [28]	PLE[3] 0.3mg (84)	47.2(12.02)	45.4(12.02)	68(81)	69(81.2)	-	-	-	-
	PLE 1 mg (83)	44.6(12.58)	45.4(12.02)	67(80.7)	69(81.2)	-	-	-	-
	PLE 3 mg (86)	47.2(12.89)	45.4(12.02)	70(81.4)	69(81.2)	-	-	-	-
	PLE 9 mg (85)	45.3(12)	45.4(12.02)	70(82.4)	69(81.2)	-	-	-	-
	PCB (85)	-	45.4(12.02)	-	-	-	-	-	-
Rao 2016 [29]	-	-	-	-	-	-	-	-	-
Miner 2017 [24]	PLE 3mg (453)	45(10.61)	46.4(10.4)	368(81.2)	357(79)	28.1(5.3)	28.1(5.3)	0.3(0.5)	0.4(0.6)
	PLE 6 mg (441)	45.1(10.61)	46.4(10.4)	357(79)	357(79)	28.2(5.3)	28.1(5.3)	0.3(0.5)	0.4(0.6)
DeMicco 2017 [25]	PLE 3mg (443)	45.5(10.79)	44.6(10.79)	345 (77.9)	350 (78.7)	28.59 (4.72)	27.97 (5.08)	0.28(0.55)	0.31(0.5)
	PLE 6 mg (449)	45.3(10.79)	44.6(10.79)	353 (78.6)	350 (78.7)	28.38 (4.86)	27.97 (5.08)	0.25(0.44)	0.31(0.5)
Fogel 2018 (a) [30]	PLE 3mg (351)	-	-	-	-	-	-	-	-
	PLE 6 mg (350)	-	-	-	-	-	-	-	-
Fogel 2018 (b) [32]	PLE 3mg (377)	-	-	-	-	-	-	-	-
	PLE 6 mg (379)	-	-	-	-	-	-	-	-
Brenner	PLE 3mg (351)	43(13.8)	43(13.7)	267 (76.1)	272 (76.8)	-	-	0.2(0.5)	0.2(0.4)
2018 (a) [31]	PLE 6 mg (349)	43.2(13.3)	43(13.7)	266 (76.2)	272 (76.8)	-	-	0.3(0.5)	0.2(0.4)
Brenner	PLE 3mg (377)	44(14.6)	44(14.7)	270 (71.6)	272 (71.8)	-	-	0.3 (0.5)	0.2(0.5)
2018 (b) [31]	PLE 6 mg (379)	43.1(14.2)	44(14.7)	273 (72.0)	272 (71.8)	-	-	0.3 (0.5)	0.2(0.5)
Brenner 2019 [32]	PLE 3mg (896)	45.2(10.2)	45.5(10.2)	713(79.6)	707(78.8)	28.35(3.6)	28.02(3.9)	-	-
	PLE 6 mg (890)	45.2(10.2)	45.5(10.2)	715(80.3)	707(78.8)	28.37(3.61)	28.02(3.9)	-	-
	PCB (897)	-	-	-	-	-	-	-	-
Bareish 2020 [26]	PLE 0.3mg (237)	47.8(10.01)	46.3(10.19)	203(75.7)	207(88.5)	-	-	-	-
	PLE 1 mg (238)	47.1(10.37)	46.3(10.19)	202(84.9)	207(88.5)	-	-	-	-
	PLE 3 mg (237)	47.1(10.37)	46.3(10.19)	205(86.5)	207(88.5)	-	-	-	-
	PCB (234)	-	-	-	-	-	-	-	-
Cash 2021 (a) [33]	-	-	-	-	-	-	-	-	-
Cash 2021 (b) [33]	-	-	-	-	-	-	-	-	-
NCT01053962 2010 [34]	PLE 0.3mg (14)	51.1(11.95)	47.7(14.64)	12(85.7)	18(90)	-	-	0.4(0.53)	0.3(0.53)
	PLE 1 mg (14)	50.5(10.6)	47.7(14.64)	14(100)	18(90)	-	-	0.6(0.74)	0.3(0.53)
	PLE 3 mg (15)	48.5(16.17)	47.7(14.64)	13(86.3)	18(90)	-	-	0.5(0.92)	0.3(0.53)
	PLE 9 mg (15)	47.3(12.7)	47.7(14.64)	12(80)	18(90)	-	-	0.4(0.54)	0.3(0.53)
	PCB (20)	-	-	-	-	-	-	-	-
NCT03120520 2019 [35]	PLE 0.5mg (31)	15.1(1.48)	14.6(1.61)	17(54.8)	17(54.8)	-	-	-	-
	PLE 1 mg (31)	14.5(1.89)	14.6(1.61)	17(56.7)	17(54.8)	-	-	-	-
	PLE 1.5 mg (30)	14.6(1.52)	14.6(1.61)	18(56.3)	17(54.8)	-	-	-	-
	PCB (31)	-	-	-	-	-	-	-	-

Study ID	Study Groups	SBMs/week(Mean/SD)		Stool Consistency (Mean/SD)		Straining Score(Mean/SD)		Abdominal Discomfort Score(Mean/SD)		Abdominal Bloating Score(Mean/SD)
		Plecanatide	Control	Plecanatide	Control	Plecanatide	Control	Plecanatide	Control	Plecanatide	Control
Miner 2013 [27]	-	-	-	-	-	-	-	-	-	-	-
Miner 2014 [28]	PLE 0.3mg (84)	-	-	-	-	-	-	-	-	-	-
	PLE 1 mg (83)	-	-	-	-	-	-	-	-	-	-
	PLE 3 mg (86)	-	-	-	-	-	-	-	-	-	-
	PLE 9 mg (85)	-	-	-	-	-	-	-	-	-	-
	PCB (85)	-	-	-	-	-	-	-	-	-	-
Rao 2016 [29]	-	-	-	-	-	-	-	-	-	-	-
Miner 2017 [24]	PLE 3mg (453)	2(1.8)	2.2(2)	2.5(1.1)	2.6(1.1)	2.3(0.8)	2.3(0.8)	1.8(0.8)	1.8(0.9)	1.9(0.9)	1.9(0.9)
	PLE 6 mg (441)	1.8(1.8)	2.2(2)	2.6(1.2)	2.6(1.1)	2.3(0.9)	2.3(0.8)	1.8(0.9)	1.8(0.9)	1.9(1)	1.9(0.9)
DeMicco 2017 [25]	PLE 3mg (443)	1.79(2.05)	1.5(1.59)	2.16(1.03)	2.35(1.9)	2.45(0.85)	2.41(0.85)	1.92(1.01)	1.9(0.99)	2.02(0.97)	2.03(0.91)
	PLE 6 mg (449)	1.6(1.66)	1.5(1.59)	2.28(1.11)	2.35(1.9)	2.47(0.88)	2.41(0.85)	2.02(0.98)	1.9(0.99)	2.1(0.97)	2.03(0.91)
Fogel 2018 (a) [30]	PLE 3mg (351)	-	-	-	-	-	-	-	-	-	-
	PLE 6 mg (350)	-	-	-	-	-	-	-	-	-	-
Fogel 2018 (b) [32]	PLE 3mg (377)	-	-	-	-	-	-	-	-	-	-
	PLE 6 mg (379)	-	-	-	-	-	-	-	-	-	-
Brenner2018 (a) [31]	PLE 3mg (351)	-	-	2.0 (0.9)	2.1(1)	6.5(1.8)	6.4(2)	6.2(1.6)	6.4(1.6)	6.4(1.7)	6.5(1.7)
	PLE 6 mg (349)	-	-	2.0 (0.9)	2.1(1)	6.5(1.8)	6.4(2)	6.2(1.6)	6.4(1.6)	6.3(1.7)	6.5(1.7)
Brenner2018 (b) [31]	PLE 3mg (377)	-	-	1.9 (0.9)	2.1(1)	6.8(1.9)	6.8(1.8)	6.6(1.6)	6.5(1.6)	6.6(1.7)	6.5(1.8)
	PLE 6 mg (379)	-	-	1.9 (0.9)	2.1(1)	6.9(1.9)	6.8(1.8)	6.5(1.8)	6.5(1.6)	6.5(1.8)	6.5(1.8)
Brenner 2019 [32]	PLE 3mg (896)	-	-	-	-	-	-	-	-	-	-
	PLE 6 mg (890)	-	-	-	-	-	-	-	-	-	-
	PCB (897)	-	-	-	-	-	-	-	-	-	-
Bareish 2020 [26]	PLE 0.3mg (237)	-	-	-	-	-	-	-	-	-	-
	PLE 1 mg (238)	-	-	-	-	-	-	-	-	-	-
	PLE 3 mg (237)	-	-	-	-	-	-	-	-	-	-
	PCB (234)	-	-	-	-	-	-	-	-	-	-
Cash 2021 (a) [33]	-	-	-	-	-	-	-	-	-	-	-
Cash 2021 (b) [33]	-	-	-	-	-	-	-	-	-	-	-
NCT01053962 2010 [34]	PLE 0.3mg (14)	2.2(1.2)	2(1.01)	2.5(0.81)	2.6(1.28)	3.1(0.64)	3(0.67)	-	-	-	-
	PLE 1 mg (14)	2.2(0.99)	2(1.01)	2.6(0.48)	2.6(1.28)	2.8(0.79)	3(0.67)	-	-	-	-
	PLE 3 mg (15)	2.1(0.93)	2(1.01)	1.8(0.69)	2.6(1.28)	2.7(0.61)	3(0.67)	-	-	-	-
	PLE 9 mg (15)	1.9(0.75)	2(1.01)	2.7(1.56)	2.6(1.28)	3(0.89)	3(0.67)	-	-	-	-
	PCB (20)	-	-	-	-	-	-	-	-	-	-
NCT03120520 2019 [35]	PLE 0.5mg (31)	-	-	2(1.19)	2.17(0.93)	-	-	-	-	-	-
	PLE 1 mg (31)	-	-	2.08(0.899)	2.17(0.93)	-	-	-	-	-	-
	PLE 1.5 mg (30)	-	-	2.29(1.298)	2.17(0.93)	-	-	-	-	-	-
	PCB (31)	-	-	-	-	-	-	-	-	-	-

Risk of Bias (ROB)

Most studies had a high risk of bias, mainly due to missing outcome data. Concerns were also noted in randomization, outcome measurement, and selective reporting domains. Five trials had low risk of bias across all domains (Figure 2).

Fig. 2.

Risk of Bias assessment using the ROB 2 tool for included randomized controlled trials. The figure summarizes bias judgments across domains such as randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of reported results

Efficacy outcomes

This meta-analysis included trials evaluating the GC-C agonist plecanatide administered at five daily doses (0.3, 1, 3, 6, and 9 mg/day). Efficacy outcomes were assessed versus placebo and across dose groups, with treatment durations categorized as long-term (12 weeks) and short-term (< 10 weeks).

Overall sustained responders

Trials [24–27, 29–31, 35] evaluated plecanatide doses of 0.3, 1, 3, and 6 mg/day for overall sustained response, defined as ≥ 30% reduction in abdominal pain and ≥ 1 increase in spontaneous bowel movements (SBMs).

All doses significantly improved overall response compared with placebo:

• 0.3 mg (RR = 0.08, 95% CI [0.03 to 0.12]; P = 0.0009),

Direct comparisons between doses showed no significant differences in responder rates (0.3 vs. 1 mg: RR = − 0.02; 3 vs. 6 mg: RR = 1.00). Heterogeneity across studies was negligible (I² = 0%). (Fig. 3; Figs. S2). (See Supplemental Index).

Fig. 3.

Forest plot of overall patient response to once-daily plecanatide (0.3, 1, 3, and 6 mg) versus placebo, showing no significant heterogeneity

Change in CSBMs per week

Changes in complete spontaneous bowel movements (CSBMs) were evaluated across all five doses in trials [24–29, 31, 34, 35].

Significant improvements versus placebo were observed for 1 mg (MD = 0.75, 95% CI [0.66 to 0.84]), 3 mg (MD = 0.92, 95% CI [0.69 to 1.14]), 6 mg (MD = 0.80, 95% CI [0.66 to 0.95]), and 9 mg (MD = 1.00, 95% CI [0.55 to 1.44]), whereas 0.3 mg showed no significant change (MD = 0.25, 95% CI [− 0.02 to 0.51]). (Figure. 4).

Fig. 4.

Forest plot of weekly change in complete spontaneous bowel movements (CSBMs) from baseline after once-daily plecanatide different doses versus placebo with corresponding heterogeneity statistics

To address heterogeneity at 0.3 mg, a subgroup analysis by patient population was performed:

CIC studies (Miner 2013, Bareish 2020, NCT01053962): pooled MD = 0.42 (95% CI 0.22–0.62), indicating consistent and statistically significant improvement.

IBS-C study (Miner 2014): MD = 0.01 (95% CI − 0.25 to 0.27), suggesting no meaningful effect.

Similar analyses for plecanatide 3 mg confirmed greater efficacy in CIC than IBS-C, which reduced heterogeneity and clarified dose-specific effects (Fig. S3). Further subgroup analysis by study phase at 3 mg showed that Phase 3 trials yielded more consistent effect estimates with lower heterogeneity, whereas Phase 2 trials demonstrated greater variability, likely due to smaller sample sizes, shorter duration, and dose-ranging designs (Figs. S3–S4).

Across three IBS-C trials (Miner 2014, Brener A, Brener B), plecanatide 3 mg consistently increased weekly CSBMs compared with placebo. The mean difference vs. placebo ranged from 0.43 to 1.47 CSBMs/week, with Miner 2014 showing the largest effect and the Brener trials showing more modest improvements, resulting in high heterogeneity (I² = 100%). Subgroup analyses by baseline CSBM, abdominal pain, or sex did not meaningfully reduce this variability; nevertheless, all studies demonstrated superior efficacy of plecanatide vs. placebo. Initial heterogeneity was reduced through subgroup analyses based on treatment duration and age, except for 9 mg due to limited number of studies, without affecting statistical significance (Figs. S4–S5).

Dose comparisons demonstrated greater CSBM improvement with 1 mg and 9 mg compared with 0.3 mg (1 mg: MD = 0.63, 95% CI [0.26 to 1.0]; 9 mg: MD = 1.16, 95% CI [1.08 to 1.23]). No significant differences were observed among higher doses (1 vs. 3 mg, 3 vs. 6 mg, or 9 vs. 3 mg). Heterogeneity across comparisons was high (I² = 90–100%), separate analysis was performed for plecanatide 0.3 mg and 1 mg, confirming the pattern of greater efficacy in CIC compared to IBS-C. heterogeneity couldn’t be resolved at comparison (3 mg Vs 9 mg) as only two studies were included (Figs S6-S7).

Change in SBMs per week

Four plecanatide doses (0.3, 1, 3, and 6 mg/day) were evaluated for weekly changes in SBMs in trials [24–27, 29, 34, 35].

All doses significantly increased SBMs compared with placebo:

• 0.3 mg (MD = 0.67, 95% CI [0.45 to 0.89]),

• 1 mg (MD = 0.97, 95% CI [0.76 to 1.18]),

• 3 mg (MD = 1.50, 95% CI [1.32 to 1.68]),

• 6 mg (MD = 1.58, 95% CI [1.31 to 1.85]). (Figure 5).

Fig. 5.

Forest plot of weekly change in spontaneous bowel movements (SBMs) from baseline after once-daily plecanatide different doses versus placebo with corresponding heterogeneity statistics

Although heterogeneity was initially high (I² = 89–100%), sensitivity analysis resolved heterogeneity for 0.3 mg/day by omitting NCT01053962 (2010) and subgroup analyses based on treatment duration, sample size, and age substantially resolved heterogeneity at doses (1, 3, and 6 mg ) without altering significance. (Figs. S8–S9).

Dose comparisons showed a significantly greater improvement in spontaneous bowel movements (SBMs) with 1 mg compared to 0.3 mg (MD = 0.44, 95% CI: 0.12 to 0.76; P = 0.007), while no significant difference was observed between the 3 mg and 6 mg doses. The heterogeneity in the 0.3 mg versus 1 mg comparison was resolved by excluding the study NCT01053962 (2010).

A meta-regression suggested baseline SBM frequency did not significantly affect treatment response. Although the model explained a substantial portion of the variance (R² = 0.88), the association between baseline SBM and the mean difference in SBM frequency was not statistically significant (coefficient = − 0.48, 95% CI: −2.69 to 1.73, p = 0.22). Given the limited number of studies included, these results should be interpreted with caution. Further research is warranted to better understand this potential relationship (. (Figs. S10- S11).

Overall patient response within 24 h

The proportion of patients achieving ≥ 1 CSBM or SBM within 24 h was evaluated for 3 mg and 6 mg/day in trials [24, 25, 31].

Both doses significantly improved early response compared with placebo:

CSBM response:

• 3 mg (RR = 1.79, 95% CI [1.52 to 2.11]; P < 0.00001)

• 6 mg (RR = 1.93, 95% CI [1.64 to 2.26]; P < 0.00001).

SBM response:

• 3 mg (RR = 1.36, 95% CI [1.25 to 1.48]; P < 0.00001)

• 6 mg (RR = 1.39, 95% CI [1.28 to 1.51]; P < 0.00001). Heterogeneity was low (I² = 0–37%). (Fig. S12).

No differences were observed between doses for either CSBM (RR = 0.93; P = 0.26) or SBM (RR = 0.97; P = 0.66). Sensitivity analysis resolved moderate heterogeneity (I² = 65%) for SBM outcomes by omitting Miner (2017).

(Fig. S13).

Change in Stool Consistency (BSFS)

All five doses [24–29, 31, 34, 35] significantly improved Bristol Stool Form Scale (BSFS) scores compared with placebo:

• 0.3 mg (MD = 0.44, 95% CI [0.31 to 0.57]),

• 1 mg (MD = 0.68, 95% CI [0.53 to 0.82]),

• 3 mg (MD = 0.76, 95% CI [0.49 to1.03),

• 6 mg (MD = 0.54, 95% CI [0.16 to 0.92]),

• 9 mg (MD = 1.09, 95% CI [0.77 to 1.41]), (all P < 0.00001).

Substantial heterogeneity was initially observed (I² = 86–100%) (Fig. 6), but was resolved through subgroup analyses based on treatment duration, patient age, and sample size. Except for dose 9 mg due to limited number of trials (Figs. S14–S16).

Fig. 6.

Forest plot of weekly change in Stool Consistency Bristol Stool Form Scale (BSFS) from baseline after once-daily plecanatide different doses versus placebo with corresponding heterogeneity statistics

Dose comparisons demonstrated significant improvements for 1 mg vs. 0.3 mg (MD = 0.34) and 9 mg vs. 0.3 mg (MD = 0.61), whereas other dose comparisons were not statistically significant. Stratified analyses by patient population indicated that the 1 mg dose consistently provided greater efficacy in both IBS-C and CIC, while the 3 mg vs. 6 mg comparison showed no meaningful difference. In CIC patients, subgroup analysis by treatment duration successfully resolved heterogeneity in the 3 mg vs. 6 mg comparison, supporting the robustness of the findings (Figs. S17–S18). These results suggest that lower plecanatide doses may achieve comparable efficacy with potentially fewer safety concerns.

Change in straining score /week

Across trials [24–29, 31, 34], significant improvements in straining score were observed only with 3 mg (MD = − 0.51) and 6 mg (MD = − 0.55) compared with placebo (both P < 0.00001).

No significant improvements were observed for 0.3 mg, 1 mg, or 9 mg. (P = 0.17, P = 0.96, and P = 0.94, respectively).

Substantial heterogeneity was present across studies through doses (I² = 96–100%) (Fig. S19), but was resolved through subgroup analyses based on sample size and participant number. (Figs. S20- S21). However, heterogeneity for the 9 mg dose could not be resolved because only two studies were included.

Dose comparisons across trials [26–28, 34] generally showed no significant differences, except for 9 mg versus 1 mg, which favored 9 mg (MD = 0.52; P < 0.00001). Heterogeneity remained high for several comparisons, particularly at doses of 0.3, 1, 3, and 9 mg, and could not be fully explored due to the limited number of studies [24, 28]. Stratified analyses by patient population for the comparisons of 0.3 mg versus 1 mg and 3 mg versus 6 mg successfully resolved the observed heterogeneity. (Fig. S22- S23).

Change in abdominal pain and bloating

Abdominal symptoms were evaluated for 3 mg and 6 mg/day in trials [24, 25, 28, 31] for abdominal pain and [24, 25, 28, 29, 31] for abdominal bloating.

Compared with placebo, 3 mg/day improved abdominal pain (MD − 0.40, P = 0.003) and bloating (MD − 0.22, P < 0.00001).At 6 mg,

6 mg/day improved bloating (MD − 0.22, P = 0.007) but not pain (P = 0.06). Despite substantial heterogeneity (I² = 100%), subgroup analyses based on sample size and patient age successfully resolved variability in bloating outcomes. For abdominal pain, separate analyses by patient population were conducted for the 3 mg and 6 mg doses.

Meta-regression indicated a negative association between baseline abdominal pain and treatment effect (β = −0.11), suggesting greater efficacy in studies with higher baseline severity; however, this finding was not statistically significant (p = 0.15) and should be interpreted cautiously given the limited number of studies. (Figs. S24- S26).

Direct comparisons between 3 mg and 6 mg in trials [24, 25, 29, 31] showed no significant differences The outcomes expressed a significant heterogeneity which could be resolved later via subgroup analyses based on patient characteristics and study design. (Fig. S27, S28).

Treatment continuation, satisfaction, and constipation severity

Two studies [24, 25] evaluated treatment continuation, patient satisfaction, and constipation severity for 3 mg and 6 mg/day. Both 3 mg and 6 mg/day improved treatment continuation, patient satisfaction, and constipation severity vs. placebo (3 mg: MD = 0.35; 6 mg: MD = 0.40) satisfaction scores (3 mg: MD = 0.60; 6 mg: MD = 0.55) and constipation severity which was the same within the compared doses (MD = − 0.40). Constipation severity showed no heterogeneity, while other outcomes demonstrated substantial heterogeneity that could not be further explored due to the limited number of studies. (Fig. S29). No differences were observed between doses (Fig. S30).

Safety outcomes

The safety analysis evaluated plecanatide at five doses (0.3, 1, 3, 6, and 9 mg/day) across short-term (< 10 weeks) and long-term (12 weeks) treatment periods. Key safety outcomes included treatment-emergent adverse events (TEAEs), serious or severe TEAEs, diarrhea, other common adverse events, and treatment discontinuation.

Patients with TEAE(s)

Across trials [24–28, 31, 32, 34, 35], plecanatide at 1 mg, 3 mg, 6 mg, and 9 mg/day was associated with a higher incidence of TEAEs compared with placebo:

• 1 mg: RR = 1.55, 95% CI [1.05–2.29]; P = 0.03

• 3 mg: RR = 1.27, 95% CI [1.07–1.52]; P = 0.007

• 6 mg: RR = 1.12, 95% CI [1.02–1.23]; P = 0.02

• 9 mg: RR = 2.48, 95% CI [1.47–4.17]; P = 0.0007.

The 0.3 mg dose showed no significant increase in TEAEs (P = 0.20). Heterogeneity was absent or low for 0.3 mg, 6 mg, and 9 mg (Figure 7), whereas moderate heterogeneity for 1 mg and 3 mg was resolved by sensitivity analyses excluding Miner (2013) and Barish (2020) (Fig. S31).

Fig. 7.

Forest plot of incidence of total adverse events (TEATs) after once-daily plecanatide different doses versus placebo with moderate heterogeneity at doses 1 and 3 mg

Dose-comparison analyses indicated that 0.3 mg and 3 mg were associated with fewer TEAEs compared with 1 mg and 9 mg, while no differences were observed between 1 mg or 3 mg versus 6 mg or 9 mg. (Fig. S32).

Patients with at least 1% TEAE(s)

All five plecanatide doses were analyzed as once-daily regimens without direct dose comparisons. None were significantly associated with adverse events reported by ≥ 1% of patients versus placebo: P-values 0.25, 0.12, 0.11, 0.10, and 0.56 for 0.3, 1, 3, 6, and 9 mg, respectively. Heterogeneity was absent for all doses except 3 mg (P = 0.01, I² = 70%), which was resolved by excluding Miner (2013). (Figs. S33 and S34).

Patients with serious or severe TEAE(s)

Serious or severe TEAEs were mainly evaluated for 3 mg and 6 mg/day in trials [24–26, 28, 31, 34]. Both doses demonstrated no significant association with life-threatening events compared with placebo, with homogeneous findings across studies. (P = 0.39, I² = 0%). (Fig. S35).

For severe treatment-related adverse events, slightly fewer cases were reported with 6 mg (34 cases) compared with 3 mg (38 cases); however, no significant difference was observed between the two doses. Additional comparisons across 0.3, 1, 3, 6, and 9 mg/day also showed no increased risk of serious adverse events, supporting the overall safety profile of plecanatide. (Fig. S36).

Diarrhea following treatment

Diarrhea was assessed in trials [24–28, 30–31, 34, 35]. When analyzed individually, all plecanatide doses were associated with a higher incidence of diarrhea compared with placebo. Most analyses showed low heterogeneity, except for the 9 mg dose(P = 0.06), where heterogeneity could not be further assessed due to the limited number of trials (Fig. 8).

Fig. 8.

Forest plot of diarrhea incidence following plecanatide administration at different doses compared to placebo

A publication bias assessment for the 3 mg dose demonstrated funnel plot asymmetry suggesting possible bias; however, Egger’s regression test was not statistically significant (Fig. S37). Dose-comparison analyses showed no significant differences between plecanatide doses (Fig. S38).

Other adverse events (headache and nasopharyngitis)

Across trials [24–26, 28, 31, 34, 35], no significant association was observed between plecanatide and headache at any dose compared with placebo, with no heterogeneity among studies. Similarly, dose comparisons showed no differences in headache incidence. (Fig. S39, S40).

For nasopharyngitis, two studies [24, 31] evaluating 3 mg and 6 mg demonstrated no significant difference compared with placebo. (Fig. S41). though fewer cases occurred with 3 mg (11 cases) compared with 6 mg (15 cases).

Withdrawal due to adverse events or diarrhea

Withdrawal due to diarrhea or other adverse events was evaluated for 3 mg and 6 mg/day in trials [24, 25, 27, 30–32]. Patients receiving plecanatide withdrew more frequently than those receiving placebo at both doses (P < 0.00001) (Fig. S42).

Most analyses showed homogeneous results, except for TEAE-related withdrawals at the 3 mg dose, which demonstrated moderate heterogeneity resolved after sensitivity analysis excluding the study by DeMicco (2017) (Fig. S43). Due to the limited number of trials, dose-to-dose comparisons could not be performed for withdrawal outcomes.

Certainty of evidence

Based on the GRADE assessment, the certainty of evidence for the primary outcomes ranged from high to low.

Plecanatide versus placebo

High-certainty evidence was observed for overall sustained responders and overall patient response within 24 h (CSBM and SBM), indicating strong confidence in the estimated treatment effects.

Moderate-certainty evidence was found for several efficacy outcomes, including SBMs, stool consistency (BSFS), straining score, abdominal pain, abdominal bloating, and constipation severity. Secondary outcomes such as treatment continuation and patient satisfaction, as well as safety outcomes including diarrhea and other adverse events (e.g., headache and nasopharyngitis), were also supported by moderate-certainty evidence. These outcomes were mainly downgraded due to inconsistency related to heterogeneity and methodological limitations across studies.

Low-certainty evidence was identified for outcomes including changes in CSBMs, overall treatment-emergent adverse events (TEAEs), serious or severe TEAEs, and patient withdrawals due to adverse events. The downgrading was primarily attributable to risk of bias, including concerns related to randomization procedures, blinding, incomplete outcome data, and selective reporting, in addition to imprecision and heterogeneity across studies.

Very low-certainty evidence was observed for patients experiencing adverse events reported in ≥ 1% of participants, reflecting combined concerns of risk of bias and imprecision, particularly due to the small number of events and limited effect sizes.

Publication bias was not formally assessed for outcomes with few studies; however, subgroup and sensitivity analyses were conducted where applicable. Overall, evidence supports the efficacy of plecanatide, though variability in safety outcomes and methodological limitations reduce confidence in some findings. [Supplemental Table 1].

Plecanatide dose-pair comparisons

In contrast, the GRADE assessment of plecanatide dose-pair comparisons showed generally lower certainty of evidence. The outcomes overall sustained responders and patient response within 24 h were rated as moderate certainty, primarily downgraded due to imprecision associated with non-significant comparisons.

For several key outcomes—including changes in CSBMs, SBMs, stool consistency (BSFS), and straining score—the evidence was rated as very low certainty. Downgrades were due to risk of bias (methodological limitations in randomization, blinding, outcome measurement, and selective reporting), inconsistency (substantial heterogeneity), and imprecision (small sample sizes and wide confidence intervals). Low-certainty evidence was reported in secondary outcomes such as abdominal symptoms, treatment satisfaction, and constipation severity. Safety outcomes—including overall TEAEs, diarrhea, and severe adverse events—were also generally rated as low to very low certainty, reflecting risk of bias, variable statistical significance, limited event rates, and the small number of contributing studies.

Formal publication bias assessment was not conducted due to the limited number of studies for each dose comparison. Overall, plecanatide may confer clinical benefits across different doses; however, the certainty of evidence remains limited for several outcomes, highlighting the need for additional high-quality randomized controlled trials [Supplemental Table 2]. A detailed summary of the GRADE assessments by outcome, comparing plecanatide with placebo and across dose groups, is provided in (Supplemental Tables 3 and 4).

Discussion

Plecanatide is a synthetic analog of uroguanylin, an endogenous ligand of the guanylate cyclase-C (GC-C) receptor, which stimulates intracellular cyclic guanosine monophosphate (cGMP) production [14]. Activation of GC-C receptors increases intracellular cGMP levels, which inhibits the luminal Na+/H+ exchanger (NHE3) and indirectly stimulates the cystic fibrosis transmembrane conductance regulator (CFTR) through phosphorylation. This coordinated mechanism enhances chloride and bicarbonate secretion while promoting water efflux into the intestinal lumen. Consequently, sodium absorption is reduced, and the secretion of Cl⁻, HCO₃⁻, K⁺, and H₂O is increased. These effects collectively improve intestinal fluid balance, soften stool consistency, and accelerate gastrointestinal transit. This mechanistic pathway directly explains the observed clinical improvements in complete spontaneous bowel movements (CSBMs), spontaneous bowel movements (SBMs), and stool consistency in patients treated with plecanatide [36–39].

Significance of the study

This study offers a comprehensive and clinically relevant evaluation of plecanatide in the management of chronic idiopathic constipation (CIC), irrespective of the coexistence of irritable bowel syndrome with constipation (IBS-C), across a range of dosing regimens. By integrating data from multiple randomized controlled trials, this meta-analysis demonstrates consistent and clinically meaningful efficacy of plecanatide, particularly at the 3 mg and 6 mg once-daily doses. Notably, the findings highlight a rapid onset of action, with measurable therapeutic benefits observed within 24 h of treatment initiation, underscoring its potential advantage in symptomatic relief.

In addition to efficacy, plecanatide exhibited a favorable tolerability profile. Although diarrhea was the most frequently reported adverse event, it was generally mild to moderate and manageable at therapeutic doses. These findings reinforce the clinical value of plecanatide as an effective and well-tolerated therapeutic option for patients with CIC and IBS-C. Furthermore, the results provide practical guidance for clinicians in optimizing dose selection and tailoring treatment strategies based on patient response and tolerability.

The summary of main findings

The present meta-analysis demonstrates that plecanatide significantly improves multiple key efficacy outcomes compared with placebo across various dosing regimens. Treatment was associated with a higher proportion of overall responders and significant improvements in CSBMs, SBMs, and stool consistency scores, reflecting robust effects on bowel function.

Additional benefits, including improvements in straining, abdominal pain, and abdominal bloating, were observed; however, these effects appeared dose-dependent and were more pronounced with specific dosing regimens.

From a safety perspective, plecanatide maintained a favorable overall profile, with relatively low rates of treatment-emergent adverse events. Nevertheless, diarrhea occurred more frequently in plecanatide-treated patients compared with placebo and represented the primary adverse event leading to treatment discontinuation. Despite this, the overall balance between efficacy and safety remains strongly supportive of plecanatide’s therapeutic role.

Discussion of results

Efficacy across multiple doses of plecanatide

Overall sustained patient response

Plecanatide improved overall sustained response rates across doses of 0.3–6 mg/day compared with placebo, consistent with findings by Barish et al. [26] and Chang et al. [40]. This meta-analysis integrates evidence across trials, demonstrating consistent benefits and suggesting a therapeutic plateau beyond certain doses.

Despite clear efficacy, direct dose-to-dose comparisons did not reveal statistically significant differences, suggesting the presence of a therapeutic plateau beyond certain dosing thresholds. The absence of heterogeneity across studies further strengthens the reliability and consistency of these findings and indicates that doses exceeding 3 mg/day may not provide substantial additional clinical benefit.

Change in Complete Spontaneous Bowel Movements (CSBMs)

Plecanatide significantly increased CSBM frequency at doses of 1, 3, 6, and 9 mg/day compared with placebo, whereas the 0.3 mg dose did not show significant improvement. This finding contrasts with Ahmed et al. [41], likely reflecting differences in study scope and sample size. By incorporating a broader evidence base, the present meta-analysis provides a more comprehensive and statistically robust estimate of treatment effect.

Consistent with Chang et al. and Menees et al. [40, 42], improvements were most evident at 3 mg and 6 mg. Notably, this analysis further clarifies that increasing the dose beyond 1 mg/day does not yield proportionally greater improvements, thereby refining the understanding of the dose–response relationship. This represents an important contribution to the literature, as it helps delineate the threshold beyond which additional dosing may not translate into clinically meaningful benefit.

Change in Spontaneous Bowel Movements (SBMs)

Plecanatide significantly increased SBM frequency across all evaluated doses compared with placebo, consistent with prior studies [40, 43]. In contrast to inconsistent findings reported by Ahmed et al. [41], this meta-analysis resolves prior uncertainty by demonstrating a clear and consistent treatment effect across dosing regimens. Furthermore, the 1 mg dose showed meaningful benefit over 0.3 mg, with no additional improvement at higher doses, further confirming the plateau effect, offers new insight into the optimal dosing range. Meta-regression suggested a trend toward greater benefit in patients with lower baseline SBM, reflecting plecanatide’s mechanism of enhancing fluid secretion and motility via GC-C activation.

Rapid onset of response

Clinically, a responder is typically defined by the absence of rescue medication use, achievement of ≥ 3 CSBMs and SBMs per week, and sustained improvement over at least 9 of 12 weeks compared with baseline [43, 44]. Early symptomatic relief within 24 h was observed, emphasizing plecanatide’s rapid onset as a key therapeutic advantage. This aligns with other GC-C agonists such as linaclotide [45, 46], reinforcing a class effect while clarifying response magnitude and consistency.

Change in stool consistency

Plecanatide significantly improved stool consistency across all evaluated doses, shifting stool form toward normalized BSFS categories. While prior studies have reported mixed findings [40–42, 47], this meta-analysis consolidates available evidence and demonstrates a consistent treatment effect across doses.

Importantly, the analysis identifies that although higher doses may produce statistically greater improvements compared with the lowest dose, differences between commonly used clinical doses were minimal., confirming a dose–response plateau [40–42]. Although higher doses showed greater improvements compared with 0.3 mg, no meaningful differences were observed between intermediate doses.

Change in straining score

A straining score is a numerical scale and a single-item part of the Patient Assessment of Constipation-Symptoms (PAC-SYM), which assesses the frequency or degree of straining during bowel movements [48, 49].

Plecanatide demonstrated improvements in straining scores, with statistically significant effects observed at 3 mg and 6 mg. While previous studies have reported conflicting results [41], this meta-analysis provides a more definitive assessment by integrating data across trials.

Improvements in straining were significant at 3 mg and 6 mg, consistent with post-hoc analyses [50] and other GC-C agonists [51]. Lower doses (0.3–1 mg) were less effective, while incremental benefits at 9 mg are limited, supporting standard dosing for clinical practice. However, the absence of direct comparisons between the 3 mg and 6 mg doses limits definitive conclusions and underscores the need for further dose-optimization studies.

Abdominal pain, bloating, and patient-reported outcomes

Abdominal pain and bloating, although both features of chronic idiopathic constipation (CIC), represent distinct clinical entities. Abdominal pain is typically localized and crampy, whereas bloating reflects a subjective sensation of fullness or pressure. Both are common in gastrointestinal disorders, particularly irritable bowel syndrome (IBS) and chronic constipation [52, 53]. Plecanatide 3 mg improved both abdominal pain and bloating, while 6 mg improved bloating only. These findings partially align with Ahmed et al. [41] and are strongly supported by pooled randomized trials demonstrating significant improvements with the 3 mg dose [54–56]. By integrating data across studies, this analysis provides a more robust and generalizable estimate of treatment effect than individual trials.

Meta-regression suggested trends toward greater benefit with higher baseline pain, though not statistically significant, potentially reflecting modulation of visceral sensitivity via cGMP. Patients with higher baseline pain may therefore derive greater benefit through both improved bowel function and reduced visceral hypersensitivity.

Treatment satisfaction, continuation, and reduced constipation severity improved with both doses, highlighting patient-centered benefits. This is the first meta-analysis to evaluate treatment continuation, adding a novel perspective to the literature [24, 42, 43, 57, 58]. Overall, this meta-analysis provides a more definitive and clinically actionable synthesis of the evidence by resolving prior inconsistencies, clearly delineating the dose–response relationship, and integrating patient-reported outcomes. Collectively, the findings support 3 mg as the optimal dose balancing efficacy and tolerability.

Safety and adverse events

Overall, plecanatide demonstrated a favorable safety profile across all evaluated doses. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, consistent with prior randomized trials [25]. Although incidence rates varied across studies, the pooled findings align with previous evidence, reinforcing the consistency and generalizability of plecanatide’s tolerability profile [56, 59]. By synthesizing data across trials, this meta-analysis provides a more robust and comprehensive assessment of safety than individual studies.

All doses were associated with TEAEs; however, the 0.3 mg dose did not significantly differ from placebo. Lower doses (0.3 mg and 3 mg) tended to be associated with fewer adverse events compared with higher doses, suggesting a potential dose–tolerability relationship. This finding contrasts with Bai et al. [59]., who reported increased adverse events with the 3 mg dose. The discrepancy likely reflects study-specific variability rather than consistent safety concerns In contrast, the present meta-analysis, through synthesis of multiple studies, suggests that plecanatide overall maintains a safety profile comparable to placebo, indicating that such discrepancies may be attributable to study-specific factors rather than consistent safety concerns. Supporting this interpretation, DeMicco et al. reported comparable TEAE rates between plecanatide (3 and 6 mg/day) and placebo [25], while Black et al. observed no significant differences between doses despite variations in overall adverse event rates, however, indirect comparisons showed no significant differences between doses, and plecanatide 6 mg ranked as the safest option based on P scores [56]. Collectively, these findings suggest that plecanatide maintains a safety profile broadly comparable to placebo across clinically relevant doses.

In analyses restricted to adverse events occurring in ≥ 1% of patients [59], plecanatide was not associated with a statistically significant increase in such events across doses. Notably, when severe or serious adverse events were considered, the 3 mg and 6 mg doses demonstrated similarly low and comparable rates. These findings are consistent with pooled trial data reporting adverse event rates of 23.5% and 22.1% for 3 mg and 6 mg, respectively [60], as well as DeMicco et al., who reported low rates of severe (1.3–1.7%) and serious adverse events (0.9–1.7%) comparable to placebo [25]. Taken together, and in line with the present meta-analysis, these results suggest that plecanatide is generally well tolerated, with serious adverse events occurring at low and comparable rates across doses.

Additional meta-analyses further support the absence of increased serious adverse events with plecanatide and other GC-C agonists [51, 61]. Collectively, these findings reinforce the safety of plecanatide and provide a more precise and evidence-integrated understanding of its adverse event profile across dosing regimens.

Regarding specific adverse events, plecanatide was not associated with an increased risk of non-gastrointestinal events such as headache or nasopharyngitis, consistent with prior reports [41, 55, 61]. In contrast, diarrhea was consistently identified as the most frequent adverse event across all doses, in agreement with previous studies [55]. This effect is mechanistically linked to GC-C receptor activation, which enhances intestinal ion and fluid secretion, increasing luminal water content. While this mechanism underlies the therapeutic efficacy of plecanatide, excessive fluid secretion in some patients may result in diarrhea. Mechanistically, this is consistent with GC-C receptor activation, which increases intestinal fluid secretion and may, in some patients, lead to diarrhea due to alterations in intestinal motility and peristalsis which enhances luminal water efflux [24–26, 59, 62, 63]. Additionally, some studies have explored the potential role of altered gastrointestinal motility; however, this mechanism remains unconfirmed and requires further research.

Treatment discontinuation was primarily driven by adverse events, particularly diarrhea. Although withdrawal rates appeared higher with the 3 mg dose compared with placebo, direct comparisons between 3 mg and 6 mg were inconclusive. Prior studies have reported similar findings, with some indicating higher discontinuation due to diarrhea at 6 mg despite comparable overall withdrawal rates [55]. Additional evidence from meta-analyses and observational studies confirms an increased risk of withdrawal due to diarrhea with plecanatide compared with placebo [16, 40, 61, 64]. Nevertheless, overall discontinuation rates remain relatively low, supporting acceptable tolerability in clinical practice. Collectively, these findings support the conclusion of our meta-analysis that diarrhea remains the principal driver of treatment discontinuation with plecanatide, while also highlighting that overall withdrawal rates are relatively low and comparable across doses, reinforcing its acceptable tolerability in clinical practice.

Based on GRADE assessment, evidence for primary efficacy outcomes ranged from high to moderate quality, supporting the robustness of clinical benefit. In contrast, safety outcomes were generally of low to very low quality due to heterogeneity, risk of bias, and limited statistical power. Similarly, comparisons between different doses were predominantly supported by low-quality evidence, with the exception of selected outcomes such as overall response and early (24-hour) response. These findings highlight the need for further well-designed, adequately powered trials to strengthen confidence in the safety profile and dose optimization of plecanatide.

Clinical implications

This comprehensive meta-analysis demonstrates that plecanatide provides consistent and clinically meaningful improvements across multiple symptoms of chronic idiopathic constipation (CIC), with or without IBS-C, compared with placebo. Plecanatide significantly increased overall response rates, improved CSBM and SBM frequency, enhanced stool consistency, and reduced straining across a broad dosing range (0.3–9 mg/day), with the most consistent and clinically relevant effects observed at the 3 mg and 6 mg once daily.

Both doses were associated with a rapid onset of action, with significant symptom improvement observed within 24 h. Despite the absence of meaningful differences between 3 mg and 6 mg across most outcomes, both doses consistently outperformed placebo while maintaining a favorable safety profile.

Improvements in abdominal symptoms and patient-reported outcomes, including treatment satisfaction and continuation, further support the clinical utility of plecanatide. Although diarrhea remains the most common adverse event, it is generally manageable and does not outweigh the overall therapeutic benefit.

Taken together, these findings support plecanatide as an effective once-daily therapy for CIC, with the 3 mg dose representing the optimal balance between efficacy, tolerability, and patient-centered outcomes in routine clinical practice.

Strengths and limitations

This meta-analysis has several notable strengths. First, it evaluated a wide range of plecanatide doses (0.3–9 mg) across multiple randomized controlled trials, enabling a robust assessment of dose–response relationships. Second, it is among the first studies to systematically compare different plecanatide doses against each other in terms of both efficacy and safety. Third, it also provides one of the most comprehensive comparisons of plecanatide doses in terms of both efficacy and safety. Collectively, this provides a detailed and multidimensional evaluation of plecanatide’s therapeutic profile.

A wide range of clinically relevant outcomes was assessed, including bowel function (CSBMs, SBMs), stool consistency, straining, abdominal symptoms, early response, and patient-reported outcomes such as satisfaction and treatment continuation. The inclusion of these patient-centered endpoints enhances the clinical applicability of the findings.

In addition, the analysis incorporated outcomes that have been less frequently evaluated in prior studies, such as early response and treatment continuation, offering a more comprehensive understanding of plecanatide’s therapeutic profile. Consistency across placebo-controlled comparisons and the use of sensitivity and subgroup analyses further strengthen the robustness of the results.

However, several limitations should be considered. Some included data were derived from gray literature, which may affect completeness and generalizability. Heterogeneity was present in several outcomes, particularly symptom-based measures, likely reflecting differences in study design, populations, and follow-up duration.

Direct comparisons between doses were not always statistically significant, limiting definitive conclusions regarding optimal dosing. In addition, data for certain doses (e.g., 0.5 mg, 1 mg, 1.5 mg, and 9 mg) and outcomes were limited, restricting comprehensive evaluation across all endpoints. Variability in adverse event reporting and reliance on patient-reported measures may also have influenced safety estimates. Furthermore, although diarrhea was the most frequently reported adverse event leading to discontinuation, its impact on long-term adherence warrants consideration.

Finally, GRADE assessment indicated that while evidence for primary efficacy outcomes was moderate to high quality, many safety and secondary outcomes were supported by low or very low certainty evidence due to risk of bias, inconsistency, and imprecision. These factors may limit confidence in some findings.

Future large-scale, well-designed randomized controlled trials are needed to confirm long-term efficacy and safety, further evaluate underexplored dosing regimens, and better define plecanatide’s role in comparison or combination with other therapies.

Conclusion

Plecanatide is an effective and well-tolerated treatment for chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C), the 3 mg once-daily dose provides the most consistent balance between efficacy and safety. Although diarrhea is the most common adverse event, it is typically manageable and does not substantially limit treatment use.

These findings support plecanatide as a valuable therapeutic option, particularly for patients who do not achieve adequate response with conventional treatments. Further research focusing on long-term outcomes, quality of life, and comparative effectiveness will help refine its role in clinical practice.

Abbreviations

CIC

Chronic Idiopathic Constipation

IBS-C

Irritable Bowel Syndrome with Constipation

GC-C

Guanylate cyclase-C

CSBMs

Complete Spontaneous Bowel Movements

SBMs

Spontaneous Bowel Movements

FGIDs

Functional Gastrointestinal Disorders

GIS

Gastrointestinal Symptoms

IBD

Inflammatory Bowel Disease

HRQoL

Health-related Quality of Life

CD

Crohn’s Disease

cGMP

Cyclic guanosine monophosphate

CFTR

Cystic Fibrosis Transmembrane Conductance Regulator

FDA

Food and Drug Administration

CC

Chronic Constipation

BSFS

Bristol Stool Form Scale

PAC-QOL

Patient Assessment of Constipation – Quality of Life questionnaire

IBS-QOL

Irritable Bowel Syndrome – Quality of Life questionnaire

TEATs

Treatment-emergent Adverse Events

MD

Mean Difference

RR

Risk Ratio

GRADE

Grading of Recommendations, Assessment, Development, and Evaluations

GIDs

Gastrointestinal Disorders

QoL

Quality of Life

AEs

Adverse Events

IBS

Inflammatory Bowel Syndrome

PAC-SYM

Patient Assessment of Constipation-Symptoms

Authors’ contributions

MMA: conceptualization and methodology. MMA, NYE: investigation and data curation. ISE: data extraction and quality assessment. MMA, ISE: Data revision. MMA: formal analysis and GRADE assessment. MMA, ISE, NYE, FB, AAY, ARA: Writing— the original draft. MMA: project administration. MMA, NYE: Writing—Review & Editing. All authors read and approved the final content.

Funding

No Funding.

Data availability

All data generated or analysed during this study are included in this published article [and its supplementary information files].

Declarations

Ethics approval and consent to participate

Not Applicable.

Consent for publication

Not Applicable.

Competing interests

The authors declare no competing interests.